HUP-46

HUP-46 is a novel small-molecule ligand of prolyl oligopeptidase (PREP) designed to modulate protein-protein interactions (PPIs) rather than acting as a simple enzymatic inhibitor. It specifically targets the interaction between PREP and alpha-synuclein (aSyn), as well as protein phosphatase 2A (PP2A), which are critical pathways in the pathogenesis of Parkinson's disease. In preclinical mouse models, HUP-46 has demonstrated the ability to reduce the accumulation of soluble and insoluble aSyn oligomers, decrease neuroinflammation by reducing TNF-alpha and iNOS-positive microglial activation, and restore autophagic flux. Unlike traditional PREP inhibitors such as KYP-2047, HUP-46 has shown superior efficacy in ameliorating behavioral deficits in viral-vector-based models of Parkinson's disease, suggesting its potential as a disease-modifying therapy.